1-substituted-5, 10-methylene-19-nor-3-keto and 3-substituted-5, 10-seco-5, 19-cyclo-delta-steroids



United States Patent 3,257,425 1-SUBSTITUTED-5,10-METHYLENE-19-NOR-3-KETO AND 3-SUESTITUTED 5,10 SECO-5,19-CYCLO- A -STERIDS Lawrence H. Knox, Mexico City, Mexico, assignor to Syntex Corporation, Panama, Panama, a corporation of Panama;

No Drawing. Filed Feb. 20, 1964, Ser. No. 346,074 The portion of the term of the patent subsequent to May 18, 1982, has been disclaimed Claims. (Cl. 260-3973) CH CHzO R Wherein X represents a cyano group, a lower alkyl, lower alkenyl or lower alkinyl radical such as methyl, ethyl, propyl, vinyl, ethinyl, propinyl, etc.; R represents lower alkyl, lower alkenyl or lower alkinyl; R represents hydrogen or an acyl radical of less than 12 carbon atoms; R represents hydrogen, lower alkyl, lower alkenyl or lower alkinyl; R represents hydrogen, hydroxy or an acyloxy group of less than 12 carbon atoms; R represents hydrogen, oc-methyl or ti-methyl and Y represents hydrogen, keto or fl-hydroxy.

The acyl and acyloxy groups above referred to are derived from hydrocarbon carboxylic acids containing less than 12 carbon atoms which may be saturated or unsaturated, of straight, branched, cyclic or cyclic-aliphatic chain, or aromatic, and may be substituted by functional groups such as hydroxy, alkoxy containing up to 5 carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino or halogen. Typical ester groups are the acetate, propionate, enanthate, benzoate, trimethylaeetate, t-butylacetate, phenoxyacetate, cyclopentylpropionate, aminoacetate, and fi-chloropropionate.

The compounds represented by A, B and C are valuable intermediates for making the corresponding l-substituted A -3-keto compounds; in addition, the compounds represented by A and D areanabolic-androgenic agents with a favorable anabolic-androgenic ratio, having antiestrogenie, anti-gonadotrophic, anti-fibrillatory and appetite stimulating properties. Furthermore, they lower the blood chloesterol level, relieve premenstrual tension and suppress the output of the pituitary gland. In addition, the compounds having a 17u-a1kenyl or alkinyl group present certain progestational activity.

The compounds represented by B and E are powerful progestational agents with good oral activity. They have also anti-androgenic, anti-gonadotrophic and anti-estrogenic properties and are very useful in fertility control.

The compounds represented by C and F are valuable cortical hormones with high anti-inflammatory, low catabolic, glycogenic and thymolytic activities. In addition, they are anti-androgenic, anti-gonadotrophic and antiestrogenic hormones.

The novel process for making l-substituted A -3-keto and 3-substituted 5,10 seco-S,19-cyclo-A -steroid compounds of the androstane and pregnane series, which is one of the objects of the present'invention is illustrated by the following sequence of reactions:

(III) In the above formulas, A represents a hydroxyl group, the grouping wherein R represents a lower alkyl, lower alkenyl or lower alkinyl group, an acetyl radical whose keto group may be protected in the starting materials as the cycloethylenedioxy derivative, and which may be further substituted at 0170: by a hydroxyl or acetoxy group; A may also represent the dihydroxyacetone side chain protected as the 17,20;20,2l-bismethylenedioxy derivative; X and R have the same meaning as heretofore indicated. In the pregnane series, R has also the same meaning as hereinbefore indicated.

In practicing the process outlinedabove, the starting materials, 5,10 methylene-19-nor-A -androsten-1713-01- 3-one, its 17 substituted derivatives, ZO-ethylenedioxy- S-lO-methylene 19 nor-A -pregnen-3-one, -ethylene-.

dioxy 5,10 methylene-19-nor-A -pregnen-17a-ol-3-one, its acetate, 17,20;20,21 bismethylenedioxy-S,IO-methylene-19-nor-A -pregnene-3-one or the 16-methyl derivatives of the pregnane compounds (I), (obtained by treatment of the corresponding 19-hydroxy-A -3-keto .compounds with 2-chloro-l,1,2-trifluoro-triethylamine or 1,1,2,2 tetrafiuoro -ethyldimethylamine in an inert organic solvent, as described in my copending patent application Serial No. 286,931 filed June 11, 1963), now US. Patent No. 3,184,484 are treated with a Grignard reagent such as methyl magnesium bromide, ethyl magnesium bromide, vinyl magnesium bromide, ethinyl magnesium bromide, propargyl magnesium bromide, etc., in an inert organic solvent such as ether, benzene, tetrahydrofuran and the like, at a temperature comprised between room temperature and reflux, for a period of time of between 1 to 6 hours, to produce a mixture of lot-substituted- 5,10-methylene-3-keto compounds (II, X'=alkyl, alkenyl, alkinyl) and 3-substituted-5,10-seco-5,l9-cyc10-A steroids (III), which is separated by chromatography.

Among the compounds obtained by such reaction there can be mentioned:

1a-methyl-5,10-methylene-19-nor-and'rostan-175-01-3- one, 1a-viny1-5,10-methylene-19-nor-androstan-175-01-3- one,

la-ethinyl-5,IO-methylene-19-nor-androstan-1713-01-3- lot-methyl- 17 ,20;20,2 l-bismethylenedioxy-S, l0-

methylene- 1 9-nor-pregnan-3-one, lot-vinyl-17,20;20,2l-bismethylenedioxy-S,lO-methylene-19-nor-pregnan-3-one, 3-methy1-5, lO-seco-S,19-cyc1o A -androstatrien- 1713-01, 3 -vinyl-5,10-seco-5,19-cyclo-A -androstatrien- -01, 3-ethinyl-5,1O-seco-S,19-cyc1o-A -androstatrien- 17,8-01, 3,17a-dimethyl-5,10-seco-5,19-cyclo-A androstatrien- 17,8-01, 3 -methyl-17a-ethiny1-5, lO-seco-S, 19-cyclo-A androstatrien- 175-01, 3-methy1-20-ethylenedioxy-5, l0-seco-5,19-cyclo- A -pregnatriene, 3-vinyl-20-ethylenedioxy-5 ,-l O-seco-S, l9-cyclo- A -pregnatriene, 3-ethinyl-20-ethylenedioxy-S, 10-seco-5,19-cyc1o- A -pregnatriene, 3-methyl-20-ethy1enedioxy-l7a-acetoxy-5,10-seco- 5,19-cyclo-A -pregnatriene, 3-methy1-17,20;20,2l-bismethylenedioxy-S, 10-seco- 5 l 9-cyclo-A -pregnatriene, 3-vinyl-17,20;20,2l-bismethylenedioxy-S, lO-seco- 5,19-cyclo-A -pregnatriene, and 3-ethinyl-17,20;20,2l-bismethylenedioxy-S,10-seco- 5,19-cyclo-A -pregnatriene.

In the case of the pregnane compounds whose ZO-keto group is protected as the cycloethyleneketal, this protecting group may be hydrolyzed by conventional methods, preferably by treatment with p-toluenesulfonic acid in acetone solution, at room temperature for a period of time in the order of 4 hours.

Upon treatment of the lot-substituted compounds (II, X=alkyl, alkenyl, alkinyl) with a mineral acid such as hydrochloric acid, sulfuric acid, perchloric acid, etc. in an alcoholic solvent such as for example using methanol, ethanol, propyl alcohol, t-butyl alcohol, e tc., preferably at reflux temperature for about 1 to 5 hours, there are produced the corresponding A -3-keto steroids (IV, X=alkyl, alkenyl, alkinyl), i.e. the la-alkyl, alkenyl and alkinyl derivatives of testosterone, 17OL-SllbStlIUtGd testosterone, progesterone, 17a-acetoxy progesterone, etc. In the case of the pregnane series, whose 20 keto group was protected in the starting materials as the cyc1oeth yleneketal, this protecting group is also hydrolyzed by the acid treatment.

Alternatively, in order to obtain the 1u,17a-dialkyl, dialkenyl or dialkinyl substituted androstane compounds, there is used 5,IO-methylene-19-nor-A -androstene-3,l7- dione as starting material, togive the 10:,17cc-di811b8titl1t8d 5,10-methylene 19-nor compounds and 3,17oz-di5ubStituted 5, 10-seco-5, 19-cyclo-A -steroids.

Upon reaction of the former with a mineral acid there are produced the corresponding 1a,17adisubstituted-A 3-keto-androstene derivatives.

By treatment of the abovementioned starting materials (I) with an alkali metal cyanide, preferably using potassium cyanide in ethanol solution, at reflux temperature for a period of time in the order of 3 hours, there are provided exclusively the 1a-cyano-5,10-methylene-l9- nor-3-keto compounds (II, X=cyano) which by 'acid treatment, as described previously for the lot-alkyl, alkenyl or alkinyl compounds, are converted into the corresponding 1a-cyano-A -3-keto steroids (IV, X=c'yam).

.In this case, there can also be used as starting materials, 5,10-methylene 19 nor-A -pregnene-3,20-dione- 5,10 methylene 19 nor-A -pregnen-l7a-ol-3,20-dione and the '16-methyl derivatives thereof, since it is not necessary to protect the 20-keto group.

The 1 substituted A -3-keto compounds obtained by this method may be converted into the 1 dehydro derivatives by conventional methods, such as for example by dehydrogenation with selenium dioxide or 2,3-dichloro- 5,6-dicyano-1,4-benzoquinone.

In the pregnane series, the bismethylenedioxy group is hydrolyzed by conventional methods, such as by reflux with 60% formic acid, to produce the corresponding compounds having the dihydroxy-acetone side chain of the corticoids; in addition, a hydroxyl group may be introduced at C-11 by incubation with adrenal glands, Curvularia lunata, etc.

Upon oxidation of the 11 hydroxylated compounds with chromic acid in aqueous acetic acid or with an 8 N solution of chromic acid in acetone, previous acetylation of the 21-hydroxy group, there are obtained the corresponding ll-keto compounds.

The compounds of the present invention having a primary or secondary hydroxyl group are conventionally esterified with acid anhydrides or chlorides of less than 12 carbon atoms in pyridine solution, to produce the 35 corresponding acylates. 1

The compounds having a teritary hydroxyl group at C-17 are esterified with carboxylic acid anhydrides of the type described hereinbefore, in benzene solution and in the presence of p-toluenesulfonic acid.

The following specific examples serve to illustrate, but

are not intended to limit the scope of the present invendistillation of 20 cc. of the solvent mixture; there was then added a solution of 2 g. of aluminum isopropoxide dissolved in 15 cc. of anhydrous tolueneand 4 cc. of cyclohexanone and the mixture. was refluxed for minutes; there was added 8 cc. of acetic acid and the solvents were eliminated by steam distillation. The product was extracted several times with ethyl acetate and the organic extracts were washed with water to neutral, dried over anhydrous sodium sulfate andevaporated to dryness. By crystallization from acetonehexane there was obtained ZO-ethylenedioxy-A -pregnen-19-01- 3-one.

To a solution of 6 g. of the latter compound in 70 cc. ofacetonitrile (distilled over phosphorous pentoxide) there was added 5 g. of 2-chloro-1,1,2-trifluorotriethylamine) N. M. Yarovenko et al., Journal of General Chemistry of the USSR, V 29, 1959 (1959) and the mixture was refluxed for 30 minutes; it was then evaporated to dryness under reduced pressure'and the residue dissolved in hexane and chromatographed on 300 g. of Florisil. The fractions eluted with hexane-ether (7:3) .gave ZO-ethylenedioxy-S,lO-methylene 19-110r-A pregnen-3-one. Further elution with the same mixture of solvents gave ZO-ethylenedioxy-S,10-seco-5,19-cyc1o- 1OB-fluoro-A -pregnen-3-one.

In a similar manner, the compounds mentioned below under I gave as final products the compounds set forth under II:

I II

17-acetate of M-pregnene- 3B,17a,19-l31l0l-20-01I6. methylene 19-n0r-A -pregnen-17 a-ol-3 one and the acetate of 20-ethylenedloxy-5,10-seco-5,19-eycl0-10fl-fiuoro- N-pregnen-197a-ol-3-one.

16a-methyl'20-ethylenedioxy-5,10-

methylene-19mor-A -pregnen-3-one and 16a-methyl-ZO-ethylenedioxy- 16a-methyl-M-pregnene-Elfl,19-

diol-20-one.

dio1-20-one. methylene-19-nor-N-pregnen-B-one and 1GB-methyl-ZO-ethylenedioxy- 5,10-seco-5,19-eyclo-l0fl-flu0ro-A pregnen-3-one. 17-acetate of lfia-methyl-A- The acetate of 16a-methyl-20-ethy1- pregneue-3fi,17a,19-tri01-20- enedioxy-5,IO-methylene-lQ-nor A one. pregnen-17a-o1-3-one-and the acetate PREPARATION II Example I A solution of 2.2 g. of 5,10-methylene-9-nor-A androsten-17fl-ol-3-one in cc. of ether was added dropwise over a 15 minute period, to 25 cc. of 4 N- methyl-magnesium bromide solution in ether, under stirring, and the reaction mixture was stirred at room temperature under anhydrous conditions'for 4 hours further. After this time it was treated carefully with saturated sodium sulfate solution and solid sodium sulfate, the inorganic material was filtered off and washed well with ether, and the filterate evaporated to dryness. The residue was chromaographed on Florisil. The fraction eluted with hexane-ether (9:1) gave 3-methyl-5,l0-seco-5,19- cyclo A fl-androstatrien-175-01; M.P. 82-84" C.; [0th, +97 (CHCl A max 215, 254 m log 6 4.21, 3.67. The fractions eluted with hexane-ether (1:1) gave IcL-methyl-S,1()-m=ethylene l9 nor androstan 17pol-3-one, M.P. 164165 C.: [041 74 (CHCl Example II A mixture of 500 mg. of Iu-methyl-S,lO-methylene-l9- nor-androstan-17/3-ol-3-one, cc. of ethanol and 5 cc. of concentrated hydrochloric acid was refluxed for 1 hour. It was then cooled, diluted with water and extracted with ether; the organic extract was washed with water, 5% sodium bicarbonate solution and water to neutral, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization of the residue from acetone-hexane gave the pure lot-methyl testosterone; M.P. 142-143 C.

kite? 242-44 m log 64.15

Example III A solution of 5 g. of 5,1O-methylene-I9-nOr-A androsten-17fi-ol3-one in 250 cc. of thiophene-free benzene The acetate of 20'ethylenedioxy-5J0- was treated with 27.5 cc. of 4 N methylmagnesium bromide in ether and the mixture refluxed with the exclusion of moisture for 3 hours. The cooled mixture was cautiously treated with excess aqueous ammonium chloride solution and the product isolated by ethyl acetate extraction. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was chromatographed on 150 g. of Florisil, to produce 1ot-methyl-5,10-methylene-19-norandrostanl7fi-ol-3-one and 3-methyl-5,10-seco-5,19-cyclo-A -androstatrien 17fl-ol-identical to the products obtained in Example I.

Example IV By following the method described in Example I, 5,10- methylene-19-nor-A -androsten-17fi-ol-3-one was treated with ethylmagnesium bromide, vinylmagnesium bromide and ethinylmagnesium bromide, to produce respectively:

10: ethyl 5,10 methylene 19 nor androstan 17eol-3-one, and 3-ethyl-5,l0-seco-5,19-cyclo-A -androstatrien 17,8 01; 1a vinyl -5,l methylene 19- nor androstan 175 ol 3 one and 3 vinyl 5,10- seco 5,19 cyclo-A androstatrien 17,8 01; letethinyl 5,10 methylene 19 nor androstan 17pol 3 one, and 3 ethinyl 5,10 seco 5,19 cyclo- A -androstatrien-17,8-01.

Example V A mixture of la-methyl-S,10-methylene-19-nor-androstan-17fi-ol-one, 4 cc. of pyridine and 2 cc. of acetic anhydride was kept at room temperature overnight,

poured into ice water, the formed precipitate was filtered, v

washed with water and dried. Crystallization from acetone-hexane gave the acetate of 1a-methyl-5,10-methylene-19-nor-androstan-17f3-ol-3-one.

In a similar manner, 3-methy1-5,10-seco-5,19-cyclo- A androstatrien 17,8 01, 1a ethyl 5,10- methylene 19 nor androstan 17 6 ol 3 one, 1apropyl 5,10 methylene 19 nor androstan 175- 01 3 one, vinyl 5,10 methylene 19 norandrostan 17/3 ol 3 one, 1a ethinyl 5,10 methylene i9 nor androstan 17B ol 3 one, 3 ethyl- 5,10 seco 5,19 cyclo-A androstatrien 17;? 01; .3 propyl 5,10 seco 5,19 cyclo-A androstatrien 17,8 ol; 3 vinyl 5,10 seco 5,19 cyclo- A androstatrien 17B 01, and 3 ethinyl 5,10- seco 5,19 cyclo-A androstatrien 17p 01, were converted into the corresponding acetates.

Example VI Example VII In the method of the preceding example there was used 70% perchloric acid instead of sulfuric acid, to produce also lot-methyl testosterone in similar yield.

8 Example VIII By following the method described in Example II, the compounds below mentioned under I were converted into the products under II.

' I II la-ethyl-S,lo-methylene-19-nor-androla-ethyl testosterone.

stan-l7fl-ol-3-one. 1a-propyl-5,10-methy1ene-19-norla-propyl testosterone.

androstan-17B-ol-3-one. 1a-vinyl-5,lO-methylene-lQ-norla-vmyl testosterone.

androstan-17fl-ol-3-one. 1a-propenyl-5,IO-methylene-lQ-norla-propenyl testosterone.

androstan-17B-ol-3-one. 1a-ethiny15,IO-methylene-lQ-norlot-ethinyl testosterone.

androstan-l7fl-ol-3-one. 1a-propinyl-5,IO-methylene-lQ-norla-propinyl testosterone.

audrostan-17fl-ol-3-one.

Example IX The compounds obtained in the preceding example were esterified with acetic, propionic and cyclopentylpropionic anhydrides, to produce the respective esters.

Example X A solution of 2 g. of lot-methyl-testosterone in 8 cc. of pyridine was treated with 4 cc. of benzoyl chloride and then heated on the steam bath for 1 hour. The mixture was then poured into ice water and the formed precipitate collected, washed with water and dried. Recrystallization from methylene chloride-hexane afforded the benzoate of lot-methyl testosterone.

Example XI 1a,17a-diethyl-5,10-methylene-l9-nor-androstan 17B ol- 3-one and 3,17a-diethyl-5,10-seco-5,19-cyclo-A -androstatrien-17501; 1 0:,17ot-diViI1Yl-5, 10-methylene-19 norandrostan-17B-ol-3-one and 3,17a-divinyl-5,10-seco-5,19- cyclo-A -androstatrien-175-01; 1a,17a-diethiny1-5,10- methylene-19-nor-androstan-17,8-01-3-one and 3,17a-diethinyl-5,1O-seco-5,19-cyclo-A -androstatrien-1713-01.

Example XII In accordance. with the method described in Example II, 1a,17a-dimethyl-5,10-methylene 19 nor androstan- 17,8-ol-3-one, 1a,17a-diethyl-5,10-methylene-19-nor-androstan-l-ol-3-one, 1a,l7a-divinyl-5,10-methylene-19-norandrostan-17fl-ol-3-one, and 1a,17a-diethi-nyl-5,IO-methylene-19-nor-androstan-17B-ol-3-one, were converted respec tlvely into 1a,17a-dimethyl-testosterone, 1a,17a-diethyl testosterone, 1a,17a-divinyl-testosterone and 1a,17adiethinyl testosterone.

Example XIII To a solution of 500 mg. of 1oc,l7 OL-dlIIlCthYltCStOSt6I'OI16 in 10 cc. of anhydrous benzene there Were added 0.1 g. of p-toluenesulfonic acidand 1 cc. of acetic anhydride and the mixture was allowed to stand for 24 hours at room temperature, poured into ice and water, and the resulting mixture stirred to effect hydrolysis of the excess anhydride. The benzene layer was separated and washed with 10% sodium carbonate solution and water. Drying, evaporation and crystallization of the residue from ether-hexane produced the acetate of 1a,17a-dimethyl-testosterone.

Example XV By following the method of Example III, the compounds below mentioned under I were treated with the I Reagent I 20-ethylenedioxy-5,IO-methylene-19-nor-A -pregnen-3-0ne.

The acetate of 20 ethylenedioxy-5,10-methy1ene-19-nor- A -pregncn-17a-ol-3-one.

2tJ-ethylcnedioxy-5,IO-methylene-19-nor-A -pregnen-3-one.

20-ethy1enedioxy-5,10-methylcne-19-nor-A -pregnen-3-one.

The acetate oi 20-ethy]enedioxy-5,10-methy1ene-19-nor- A -pregnen-17a-ol-3-0ne.

The acetate of ZO-ethylenedioxy-5,IO-methylene-lQ-nor- A -prcgnen-17a-ol-3-0ne.

17,20;20,21-hismethylenedioxy-5,10-methylene-19-nor- A -pregnen-E-one.

17,20;20,21-bismethy1enedioxy-5,10-methylene-19-nor- A -pregnen-3-one.

17,20;20,21-bismethylenedioxy-5,10-methylene-19n0r- A -pregnen-li-one.

Ethylmagncsium bromide.......

Propylmagnesium bromide Vinylmagnesium bromide Ethinylmagnesium bromide....-

Vinylmagnesium bromide Propargylmagnesium bromide- Methylmagnesium bromide.

Vinylmagnesium bromide Ethinylmagnesium bromide-.

1a-ethyl-20-ethylenedioxy-5,10-methy1ene-19-norpregnan-3-oneand 3-ethyl-20-ethylenedioxy-5,10- seco-5,19-cyclo-A -prcgnatriene.

The acetate of1a-propy1-20-ethylenedioxy-5,10-methylene-19-nor-pregnan-1 7a-o1-3-one and the acetate ot 3-propyl-2O-ethylencdioxy-5,10-seco-5,19-cyc1o-A prcgnatrienJOa-ol- 1a-vinyl-20-ethylenedioxy-5,IO-methylene-lQ-norpregnan-B-one and 3-vinyl-20-ethy1enedi0xy-5,IO-seCo- 5,19-cyc1o-A -pregnatriene.

1a-ethinyl-20-ethylenedioxy-5,IO-methyIene-lQ-norpregnan-Ii-one and 3-ethinyl-20-ethylenedioxy-5,10- seco-5,l9-cyclo-A -pregnatriene.

The acetate of 1a-vinyl-20-ethylenedioxy-5,IO-methylene- 19-nor-pregnan-17a-o1-3-one and the acetate of 3-vinyl- 20-ethylenedioxy-5,1O-seco-5,19-cyclo-A -pregnatrien-17a-ol.

The acetate of 1wpropinyl-20-ethylenedioxy-5,10-

methylene-l9-nor-pregnan-l7a-ol-3-one and the acetate i 3-propinyl-20-ethy1enedioxy-5,10-seco-5,19-

' cyclo-A -pregnatrien-17a-ol.

1iz-methyl-17,20;20,21-bismethylenedioxy-5,10-methylene- 19-nor-pregnan-3-one and 3-methyl-17,20;20,21- bismethylenedioxy-5,10-seco-5,19cyclo-A pregnatriene.

1a-vinyl-17,20;20,2l-bismethylenedioxy-5,Iii-methylene- 19-nor-pregnan-3-one and 3-vinyl-17,20;20,21- bismethylenedioxy-5,10-seco-5,Bicycle-A pregnatriene.

1a-ethinyl-17,20;20,21-bismethylenedioxy-5,Ill-methylene- 19-nor-pregnan-3-one and 3-ethinyl-17,20;20,2lbismethylenedioxy-5,10-scco-5,19-cyclo-A pregnatriene.

lfia-methyl-ll,20;20,21-bismethylenedioxy-5,IO-methyl- Methylmagnesium bromide. 1a,16a-dimethyl-17,20;20,21-b1smethylenedioxy- 1 .3- 5, 10-methylene-19-nor-pregnan-3-onc and 3,1601- d1methyl-17,20;20,2l-b1srnethylenedioxy-5,IO-seco- 5,19-cy clo-A -pregnatriene. 16a-methyl-20ethy1enedi0xy-5,IO-methylene-lQ-nonA ..-..do 1a,16a-d1methy1-20- tl1yl ned10xy-5,10-methylene-19- pregnen-3-one.

16cit-methyl-20-ethy1enedioxy-5,10-methy1ene-19nor-A pregnen-B-one.

1GB-methy1-20-ethylenedioxy-5,IO-methylene-lQ-nor-A pregnen-S-one.

The acetate of 16a-methy1-20-ethy1enedioxy-5,10-mcthylene-19-nor-A -pregnen-17a-ol-3-one.

The acetate of 16a-methyl-ZO-ethylenedioxy-5,10-methy1- ene-19-nor-A -pregnen-17a-ol-3-0ne.

Ethinylmagnesium bromide...

Ethylmagnesium bromide Vinylmagnesium bromide Methylmagnesium bromide.

Vinylmagnesium bromide nOr-pregnan-B'one and 3,IGa-dimethyI-ZO-ethylenedioxy-5,10-seco-5,19-cyclo-A -pregnatriene.

1a-cthinyl-l6a-rnethyl-20-ethylenedioxy-5,IO-methylene- 19-nor-pregnan-3-one and 3-ethinyl-16a-methyl-20- ethylenedioxy-fn,10seco-5,19-cyclo-A -prcgnatriene.

1a-ethyl-16fi-methy1-20-ethy1enedioxy-5,10-methylene- 19-nor-pregnan-3-onc and 3-ethyl-l6B-rnethyl-20- ethylenedioxy-Ea,10-seco-5,19-cyelo-A (1)? pregnatriene 1a-vinyl-1(S S-methyl-20-ethylenedioxy-5,IO-methylene- 19-nor-pregnan-3-one and 3-viny1-16fi-methyl-20- ethylcnedioxy-S, 10-seco-5,19-cyclo-A -pregnatriene.

The acetate oi 1a,16a-dimethyl-20-ethylenedioxy-5,10-

methy1ene-19nor-pregnan-l7m0l-3one and the acetate of 3,16a-dimethy1-20-ethylenedioxy-5,10-seco- 5,19-cyclo-A -pregnatrien-17a-ol.

The acetate of 1a-vinyl-loa-methyl-ZO-ethylenedioxy- 5,lfl-methylenel9-nor-preg11ai1-17a ol-3-one and the acetate of 3-vinyl lfia-methyl-ZO-ethylenedioxy-5,10- seco-5,19-cyel0-A -pregnatrien-lh-ol.

Example XIV By following the method of Example III, 2 g. of 20- ethylenedioxy-S,10-methylene l9-nor A pregnen-B-one were treated with methylmagnesiurn bromide in ether to produce a mixture of 1umethyl-20-ethylenedioxy-5,10- methylene-l9-nor-pregnan-3-one and 3-methyl-20-ethylenedioxy-5,10-seco-5,19 cyclo -'A pregnatriene, which was separated by chromatography on Florisil.

A solution of 750 mg. of 1a-methyl-20-ethylenedioxy- 5,10-methylene-19-nor-pregnan-3-one in 100 cc. of ethanol and 0.5 cc. of 70% perchloric acid was refluxed for 1 hour. It was then poured into ice water, extracted with methylene chloride and the organic extract washed with water, 5% sodium bicarbonate solution and water to neutral, dried over anhydrous sodium sulfate and evaporated to dryness.

Crystallization of the residue from acetone-ether gave the indicated Grignard reagent, to produce the compounds listed under H, which were separated by chromatography.

Example XVI In accordance with the method described in Example II the compounds listed below under I were treated with hydrochloric acid in ethanol solution, thus affording the compounds under II:

pregnan-17a-ol-3-one.

The acetate of 1a-propinyl-20- la-propinyl-17a-aeetoxyprogesethylenedioxy-5,10-methylene-19- terone. nor-pregnan-l7a-ol-3-one. 1a-methyl-17,20;20-2l-bismethylene- 1(1-methy1-17,20;20,21-bismethyldioxy-5,IO-methylene-lQ-norpregnan-3-one.

1a,16a-dimethyl-17,20;20,21-bismethylenedioxy-5,lo-methylene- 19-nor-pregnau-3-one.

1a-vinyl-17,20;20,21-bismethylenedioxy-5,10-methylene-19-norpregnan-3-one.

1a-ethiny1-17,20;20,21-bismethylenedioxy-5,10-methy1ene-19-norpregnant-one.

enedioxy-A' pregnen-3-o11e.

la-vinyl-17,20;20,21-bismethylenedioxy-A pregnen-ii-one.

1a-ethinyl-17,20;20,21-bismethylenedioxy-N-pregnen-3-one.

1u,16a-dirnethyl-20-ethy1enedioxy- 5,10-methylene-19-nor-pregnan-3- one.

1a-ethinyl-16a-methyl-ZO-ethyIenedioxy-5,IO-methyIene-lQ-norpregnan-3-one;

1a-ethyl-16fl-methyl-20ethylenedioxy-5,10-methylene-19-norpregnan-3-one.

1a-vinyl-l6B-methyl-20-ethylenedioxy-5,IO-methylene-lQ-norpregnan-B-one.

The acetate of la,16t-dimethyl-20- ethylenedioxy-5,l-methylene-l9- nor-pregnan-17a-o1-3-one.

lhe acetate of la-vinyLlM-methyl- 20-ethylenedioxy-5,IO-methylene- 19-nor-pregnan-17a-01-3-one.

Ia-IG-dimethyl progesterone.

la-ethinyl-lfia methyl pregesterone.

la-ethyl-lfifl-methyl progesterone.

la-vinyl-lfifi-methyl progesterone.

The acetate of 1a,16a-dimethyl- 17a-hydroxy-progesterone.

The acetate of lot-Vit'lYl-lficzmethyl-lM-hydroxy-progesterone.

Example XVII A mixture of 2 g. 5,1O-methylene-19-nor-A -androsten- 17fi-ol-3-one, 4 g. of potassium cyanide and 100 cc. of 95% ethanol was refluxed for 3 hours, cooled, diluted with'water and the reaction product extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization of the residue from acetone-hexane gave 1a-cyanO-S,10-methylene-19-nor-androstan-17/3-o1-3-one.

By the same method, the compounds mentioned below under Iwe-re converted into the products listed under II:

l7a-methyl-5,10-methylene-19- nor-A -androsten-17fl-ol-3-one.

17a-vinyl-5,IO-methylene-lQ-nor- A -andr0sten-17B-ol-3-one.

17a-ethinyl-5,10-rnethylene-19-nor- A -androsten-17fl-ol-3-one.

5,lo methylene-19-nor-A -pregnene- 3,20-dione.

17,20;20,2l-bismethylenedioxy- 5,1O-methylene-l9-nor-A pregnen-3-o11e.

16a-methyl-5,10-methylene-19- nor-A -pregnene-3,20-dione.

The acetate of 5,10-methylene 19- nor-A -pregnen-17a,ol-3,20- dione.

The acetate of 16a-methyl-5,10- methylenc-l9-nor-A -pregnen- 17cz-01-3,20-di0l16.

1u-cyano-17a-methyl-5J0- methylene 19-nor-androstan- 17fl-ol-3-one.

1a-cyano-17a-vinyl-5,IO-methylene-lQ-nor-androstan-l7B-ol-3- one.

la-cyano-l7a-ethinyl-5,10-

methylene l -nor-androstan- 17fl-ol-3-one.

1a-cyauo-5,10-methylene-19- nor-pregnane-3,20-dione.

la-cyano-l7,20;20,2l-bis-methylenedioxy-5,IO-methylene-lQ- nor-pregnan-B-one.

1a-eyano-16m-methyl-5J0- methy1ene-19-nor-pregnane- 3,20-di0ne.

The acetate of 1a-cyano-5,l0-

methylene-19-nor-pregnan-17aol-3,20-dione.

The acetate of la-cyano-lfiotmethyl-5,IO-methylene-lQ-norpregnan-17a-0l-3,20-dione.

Example XVIII 'I he compounds obtain-ed in the preceding example were treated with hydrochloric acid in ethanol solution, in accordance with the method of Example II, to produce respectively:

la-cyano-testosterone,

1 a-cyano-17a-methyl-testosterone, 1u-cyano-17a-vinyl-testosterone,

l acyano-progesteron e,

' 1a-cyano-17a-ethinyl-testosterone,

1a-cyano-17,20;20,21-bismethylenedioXy-A -pregnen-3- one,

let-cyano-16oc-methyl-progesterone, 1u-cyano17a-acetoxy-progesterone, lot-cyano-16a-methyl-17a-iacetoxy-progestelrone.

Example XIX A solution of 500 mg. of 1a-methyl-20-ethylenedioxy- 5,lO-rnethylene-19-nor-pregnan-3-one, in 30 cc. of acetone was treated with 50 mg. of p-toluenesulfonic acid, and the reaction mixture was kept at room temperature for 4 hours. It was then poured into ice water, extracted with ethyl acetate and the organic extract washed with water to neutral, dried and evaporated to dryness. Addition of ether gave 1a-methyl-5,l0-methylene-19-norpregnane-3,20-dione.

In a similar manner,' the acetate of IaanethyI-ZO-ethy1enedioxy-5, 10-methy1ene-19-n'orpregnan-17a-ol-3 -one, 1wethinyI-ZO-ethylenedioxy-S ,10-methy1ene-19-norpregnan-3-ione,

the acetate ot 1a,16a-dimethyl-20 ethylenedioxy-5,10-methylene-19-norpregnan-17oc-ol-3 one,

3-methyl-2O-ethylenedioxy-5,10-seco-5,19-cyclo-A pregnatriene and 3 -methyl-20-ethylenedioxy-17-acetoxy-5,10-seco-5,19-

cycl c-A -pregnatriene were converted respectively into the acetate of Ia-methyl-S, l O-methylene-19-nor-pregnan-17ix-ol-3,20-

dionc, 1a-ethinyl-S;IO-methylene-19rnor-pregnane-3,20-dione,

the acetate of 10,16oz-dlIIl6'thYl-5 ,10-methylene-l9-nor-pregnan- 17u-ol- 3,20-dione, 3-melthyl-5,104seco-5,19-cyclo-A -pregnatrien-20-one and the acetate of 3- methyl-5,10-seco-5,19-cyclo-A 1 -pregnatrien-17aol-20-one.

Example XX lot-vinyl-17a acetoxy-progesterone, 1a,16a-dimethy-l-17a-acetoxy-progesterone, lot-cyano-17a-acetoxy-pro=geste r0ne,

the acetate 1a-cyanO S,1O-methylene-l9-nor-pregnan-17a-o1-3,20-

dione Y and the acetate of 10,16a-dimethyl-5,1O-methylene-l9nor-pregnan-17a-ol- 3,20-dione were converted into the corresponding free compounds, namely,

1 u-vinyl- 17 u-hydroxy-ptrogesterone, 1oz,1'6a-dimethy1-17a-hydroxy-progesterone, 1 a-cyan o-l 7ot-hydroxy progesterone, 1a-cyano-5,'10 methylene-19-nor-pregnan-17u-ol-3 ,20-

dione and 1 ,a16a-dimethyle5,10-methylene 19-nor-pregnan-1711-01- 3,20-dione.

Example XXI By fiollowing the method of Example XIII, the compounds obtained in the preceding example were esterified with p-ropionic, caproic and cyclopentylpropionicanhy-, drides, to produce the corresponding 17 propionates, caproates and cyclopentylpropionates.

Example XXII A mixture of 1 g. of 1a-methyl-17,20;20,21bis-methylenedioxy-S,lO-methylene-19-nor-pregnan-3-one and 20 cc. of 60% formic acid was heated .on the steam bath for 1 hour, cooled, diluted with water and the formed precipitate collected by filtration, washed with water, dried and recrystallized from acetone hexane, to produce 1amethyl 5,10 'methylene-19-nor-pregnane-17a,2l-diol- 3,20-dione.

By the same method, the compounds listed below under I were converted into the products mentioned under II:

I II

1a'vinyl-5,10,1nethy1ene-19-norpregnane-17a,21-diol-3,20-dione.

la-ethinyl-5,IO-methylene-lQ-norpregnane-17a,2l-diol-3,ZO-dione.

3-methy1-5,10-seco-5,19-cyclo A100) pregnatrien-17a,21-dio1- 20-one. 3-ethinyl-5,10-sec0-5,19-cyc10- A100) -pregnatrien-l7a,21-diol- 20-one. la-cyano-5,10-methy1ene-19-norpregnane-Ha,21-dil-3,20-dione.

1a-vinyl-17,20;20,2l-bismethylenedioxy-5,lO-methylene-lQ-norpregnan-3-one. la-ethinyl-17,20;20,21-bismethylenedioxy-5,IO-methylene-lQ-norpregnan-3-one. 3Fm ethyl-17,20;20,21-bismethy1ened1oxy-5,10-seco-5,19-eyclo- A100) pregnatriene. 3-ethinyl-l7,20;20,21-bismethy1enedi0xy-5,10-sec0-5,19-eyelo- A -pregnatriene. 1a-cyan0-17,20;20,21-bismethylenedioxy-5,10-methylene-19-n0rpregnan-3-one.

1a-methyl-17,20;20,21-bismcthylla-methyl-A -pregnene-17 z,21-

enedioxy-A pregnen fi-one. diol-3,20-dione.

1a-vinyl-17,20;20,21-bismethylene 1a-vinyl-N-pregnene-Hafll-dioldioxy-A' -pregnen-3-one. 3,20-dione 1a,1Ga-dimethyl-M-pregnene-I7a,

21-dio1-3,20-dione.

la-ethinyl-N-pregnene-lhflldiol-3,20-dione.

104,16a-dimethyl-17,20;20,21-bis methylenediOXy-A pregneu-K- one. 1aethiny1-17,20;20,21-bismethylenedioxy-A pregnen-3-one.

Example XXIII A strain of Curvularia lunata ATCC 13935 was grown in a Sabourini-glucose-agar medium (Difco). The growth obtained after incubating for a week at 25 C. was suspended in 5 cc. of sterile Water. This suspension was divided in 5 portions of 1 cc. each which were employed for inoculating S-Erlenmeyer flasks of 250 cc. capacity containing each 50 cc. of a culture medium of the following composition:

Glucose 20 (NH HP0 5 NaNU 3 ,K HPO 1 MgSo .7H O 0.2 KCl 0.5 ZnSO Traces FeSO .7I-I O Traces Distilled water to complete 1 it.

i The cultures were incubated under rotatory stirring for 72 hours at 25 C. The growth was homogenized for 1 minute in a Waringblendor; 2 cc. portions of the suspension thus obtained were employed for inoculating approximately 100 Erlenmeyer flasks containing the same medium described above. The mixtures were incubated for 24 hours under rotatory stirring at 25 C. and 280 rpm; to each flask there was added 0.5 cc. of a solution of 0.5. g. of 1a-methyl-5,10-methylene-19-nor-pregnane-17a,21-diol-3,20-dione, in 50 cc. of 95% ethanol and the incubation was continued under the same conditions for 48 hours. The contents of the flasks were combined and extracted with four portions of methylene chloride. The combined extract was dried over anhydrous sodium sulfate and concentrated at low temperature to a volume of 25 cc. This solution was adsorbed on 4 g. of silica gel and eluted with methylene chloride-ether (9:1) to produce 106 methyl 5,10 methylene 19 nor preg nane-l 1B,17oc,21-triO1=3,20-di0116.

In a similar manner, the rest of the compounds obtained in the preceding example were converted into the corresponding 11/3-hydroxylated compounds, namely:

Ia-vinyl-S,10-methylene-l9-nor-pregnane- 11,8, 17a,2 l-triol-3,20-dione 1a-ethiny1-5,10-methylene-l9-nor-pregnane- 1 1B,17m,21-triol-3,20-dione 3-methyl-5 10-seco-5 19-cyclo-A -pre gnatriene- 11B,17 t,21-triol-20-one 3-ethinyl-5,10-seco-5,19-cyclo-A -pregnatriene- 11B,17a,21-triol-20-one By following the method of Example V, 500 mg. of 10:- methyl 5,10 methylene 19 nor pregn-ane 115,170,- 21-tri0l-3,20-dione were converted into its 21-monoacetate.

The foregoing compound was dissolved in 10 cc. of acetone, cooled to 0 C. and treated under an atmosphere of nitrogen and with stirring, with a solution of 8 N chromic acid (prepared by mixing 26 g. of chromium trioxide with 23 cc. of concentrated sulfuric acid and diluting with water to 100 cc.), until the color of the reagent persisted in the mixture. It was stirred for 5 minutes further at '0-5" C. and diluted with water. The precipitate was collected, washed with water and dried under vacuum, thus affording the 21-acetate of lot-methyls 5,10 methylene 19 nor pregnane 1711,21 diol- 3,11,20-trione;

. Example XXV The preceding example was repeated but using 1a,17a-dimethyl-testosteroneace- Ia-ethinyI-S,IO-methylene-19-nor-pregnene- 1 1B,17a,21-triol-3,20-dione 1a-ethinyl-A -pregnene-1 113,17a,21-triol-3,20-dione and 3-methyl-5 IO-seco-S, 19-cyclo-A -pregnatriene- 11,8,17a,21-triol-3,20-dione as starting materials. There were thus obtained as final products la-ethinyl-S, IO-methylene-19-nor-pregnane- 17a,21-diol-3,11,20-trione-21-acetate la-ethinyl-A -pregnene-17a,21-diol-3,11,20-tri0ne- 21-acetate and 3-methyl-5,10-seco-5,19-cyclo-A pregnatriene- 17a,21-diOl-3,1 1,20-trione 21-acetate respectively.

EXAMPLE XXVI I II l-vinyl-A -androstadien-17B-ol-3- one. l-ethinyl-A -androstadien-17B-0l- -one 1,17a-dimethyl-A -androstadien- 17B-o1-3-one acetate.

lot-vinyl testosterone la-ethinyl-testosterone tate la-methyl-progesterone 1a-propyl-17u-aeetoxy-progesterone.

101,16a-dimethyl-progesterone la-ethinyl-lfia-methyl-progesterone 1a-ethinyl-N-pregnene-l7a,21-diol- 3,11,20-trione-21-acetate.

l-methyl-A -dehydro-progesterone.

l-propyl l-17a-acet0xy-A -dehydro progesterone. 1,16a-dimethyl-A -dehydro-progesterone. l-ethinyl-lfia-methyl-A -dehydroprogesterone. l-ethinyl-A -pregnadiene-17a,21-

diol-3,11,21-trione-21-aeetate.

' l 5 Example XX V 'll By following the method of Example XIX, 3-ethinyl- 20-ethylenedioxy-5,10-seco, 5,19-cyclo A pregnatriene, 3-propyl-20-ethylenedioXy-5,l0-seco 5, 19 cyclo- A -pregnatrien-17a-ol-acetate and 3-vinyl-20-ethylenedioxy-5,1O-seco-S,19-cyclo-A pregnatriene were converted respectively into 3-ethinyl-5,10-seco-5,19-cyclo- A -pregnatrien20-one, 3 propyl 5,10 seco 5,19- cyclo-A -pregnatrien-17a-ol-20-one acetate and 3- vinyl-5,1O-seco-5,19-cyclo-A -pregnatrien-20-one.

I claim:

1. A compound of the following formula:

wherein X is selected from the group consisting of lower wherein R is selected from the group consisting of lower alkyl, lower alkenyl and lower alkinyl; R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl radical of less than 12 carbon atoms; and R is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl and lower alkinyl.

6. 3-methyl-5,l0 seco 5,19 cyclo statrien-17/3-ol.

7. 3,17a-dimethyl 5,10 seco 5,19 cyclo A androstatrien-17fi-ol.

8. A compound of the following formula:

1(1o), andro- If g iiz.

wherein X is selected from the group consisting of lower alkyl, lower alkenyl, lower alkinyl and cyano; R is selected from the group consisting of hydrogen, hydroxy and an acyloxy group of less than 12 carbon atoms and R is selected from the group consisting of hydrogen,

u-met-hyl and fl-methyl. 9. 1a-methyl-5,10-methylene 19 nor pregnane-3,20- dione.

16 Y 10. 1a-cyano-5,10-methylene-19 nor pregnane 3,20- dione.

11. laamethyl-ilO methylene 19 nor pregnan-17orol-3-one-acetate.

12. A compound of the following formula:

5,19 cyclo 1110191214 pregnatrien-17u-ol-20-0ne acetate.

15. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl radical of less than- 12 carbon atoms; R is selected from the group consisting of hydrogen, a-methyl and ,B-methyl, X is selected from the group consisting of lower alkyl, lower alkenyl, lower alkinyl and cyano and Y is selected from the group consisting of hydrogen, fi-hydroxy and keto.

16. lot-methyl 5,10 methylene 19 nor pregnane- 11B,170:,21-1Ii01-3,20-d10l16.

17. lot-cyano 5,10 methylene l9 nor pregnancc,2ldi0l3,20-di0l16.

18. A compound of the following formula:

wherein R is selected from the group consisting of lower alkyl, lower alkenyl and lower alkinyl; R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl radical of less than 12 carbon atoms; R is selected from the group consisting of hydrogen, ocmethyl and B-methyl; and Y is selected from the group consisting of hydrogen, p-hydroxy and keto.

19. 3 methyl 5,10 seco 5,19 cyclo A pregnatriene-l15,17a,21-triol-3,20-dione.

20. A process for making lot-substituted A -3-keto steroid compounds of the androstane and pregnane series, said substituent being selected from the group consisting of lower alkyl, lower alkenyl, lower alkinyl and cyano, Which comprises treating the corresponding 5,10-methyl- CHzOR' ene-19-nor-A -3-keto compound with a reagent selected from the group consisting of hydrocarbon magnesium halide and alkali metal cyanides in an inert organic solvent, and thereafter subjecting the l-substituted 5,10- methylene-19-nor-3-keto saturated compounds thus produced to treatment with a mineral acid in a lower aliphatic alcohol.

21. A process in accordance with claim 20 wherein the hydrocarbon magnesium halide is methyl magnesium bromide. 10

22. A process in accordance with claim 20 wherein the hydrocarbon magnesium halide is vinyl magnesium bromide.

23. A process in accordance with claim 20 wherein the hydrocarbon magnesium halide is ethinyl magnesium bromide.

24. A process in accordance with claim 20 wherein the 5 alkali metal cyanide is potassium cyanide.

25. A process in accordance with claim 20 wherein the mineral acid is hydrochloric acid.

No references cited.

LEWIS GOTTS, Primary Examiner.

HENRY A. FRENCH, Assistant Examiner. 

8. A COMPOUND OF THE FOLLOWING FORUMLA: 